Arylpyrrolopyridine derived compounds as LRRK2 inhibitors

ABSTRACT

The present invention is directed to arylpyrrolopyridine derivatives of formula (A) (A). The compounds are considered useful for the treatment of diseases associated with LRRK2 such as Lewy body dementia, Parkinson&#39;s disease cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a §371 U.S. National Stage Application of PCTInternational Application No. PCT/EP2014/057482, filed Apr. 14, 2014,which claims the benefit of priority under 35 U.S.C. §119(a)-(d) ofDanish Application No. PA201300231, filed Apr. 18, 2013. Each of theseapplications is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to arylpyrrolopyridine derivatives whichare LRRK2 inhibitors and thus useful in therapy and to pharmaceuticalcomposition comprising said compounds.

REFERENCE TO SEQUENCE LISTING

This application includes one or more Sequence Listings pursuant to 37C.F.R. 1.821 et seq., which are disclosed in both paper andcomputer-readable media, and which paper and computer-readabledisclosures are herein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Parkinson's disease is a neurodegenerative disease. It is the secondmost common neurodegenerative disease after Alzheimer's disease andaffects more than 1% of the population above the age of 65. Parkinson'sdisease is clinically characterised by resting tremor, bradykinesia andmuscular rigidity. Pathologically, the disease is characterised by lossof dopaminergic neurons with the consequent decrease in dopamine levelsin the brain and by aggregation of the protein α-synuclein in thedopaminergic neurons. These aggregations called Lewy-bodies are composedof insoluble α-synuclein phosporylated at serine-129 and ubiquitin.Current Parkinson's disease therapeutic intervention strategies aim atincreasing the dopamine levels in areas innervated by dopaminergicneurons in the brain. Levadopa is a precursor of dopamine, and it istherapeutically used to increase dopamine levels. Carbidopa is aninhibitor of the enzyme aromatic-L-amino-acid decarboxylase also knownas DOPA decarboxylase, and it is often co-administered with levadopa toincrease the fraction of levadopa which reaches the clinically relevantregions in the brain. Monoamine oxidase B inhibitors are administered toincrease the levels of dopamine by blocking the metabolism of dopamine.As an alternative, dopamine agonists are administered to stimulatedopaminergic neurons, an effect similar to that obtained by increasingthe dopamine levels. Although these therapies provide significantsymptomatic benefit to the patient, they are also associated withadverse side effects and often become ineffective after prolongedtreatment. Importantly, neither of the existing therapies addresses theunderlying and disease causing problem, i.e. the progressive loss orinactivation of dopaminergic neurons.

Leucine-Rich Repeat Kinase 2 (LRRK2) is a 2527 amino acid proteininvolved in catalysing phosphorylation and GTP-GTD hydrolysis. The NCBIreference sequence for human LRKK2 mRNA is NM_198578.2. Evidence ismounting showing a relationship between LRRK2 and the pathogenesis ofParkinson's disease. It has been shown that LRRK2 phosphorylatesα-synuclein at serine-129, and as discussed above this phosphorylatedform constitutes a significant part of the Lewy-bodies [Biochem BiophysRes Comm., 387, 149-152, 2009]. Additionally, single nucleotidepolymorphisms in functional domains of LRRK2 have been shown to causefamiliar and sporadic Parkinson's disease. So far at least 6 pathogenicvariants have been identified, i.e. Gly2019Ser, Ile2020Thr, Arg1441Cys,Arg1441Gly, Arg1441His and Tyr1699Cys [Parkinsonism Rel. Dis., 15,466-467, 2009; Movement Dis., 25, 2340-2345, 2010; Neuron, 44, 601-607,2004; and Lancet, 365, 412-415, 2005]. Importantly, the clinicalfeatures of Parkinson's disease associated with LRRK2 mutations cannotbe distinguished from those featuring in idiopathic Parkinson's disease.This strongly suggests a common pathogenic mechanism and that LRKK2activity is a rate-limiting factor in Parkinson's disease progression[FEBS Journal, 276, 6436-6444, 2009].

The most common pathogenic form of LRRK2-associated Parkinson's diseaseis found in carriers of the amino acid substitution Gly2019Ser in thekinase domain of the LRRK2 protein. Gly2019Ser Parkinson's disease isinherited in an autosomal dominant fashion suggesting a gain-of-functionmutation of the LRRK2 protein. In support of this notion, biochemicalstudies have shown that both the glycine to serine substitution at aminoacid position 2019 as well as isoleucine to threonine substitution atamino acid position 2020 in the kinase domain lead to an increasedkinase activity of LRRK2 [Proc. Nat. Acad. Sci USA, 102, 16842-16847,2005]. This suggests a causal involvement of overactive LRRK2 in thepathogenesis of familiar forms of Parkinson's disease. Thus, inhibitorsof LRRK2, including e.g. the G2019S and I2020T mutations, could be usedas disease modifying treatment in familiar Parkinson's disease.

In cellular and animal studies several phosphorylation sites in theLRRK2 protein have been identified. Most prominent, phosphorylation ofLRRK2 at two conserved residues serine at amino acid position 910 andserine at amino acid position 935 in human LRRK2 located just aminoterminal to the leucine-rich repeat domain mediates binding to 14-3-3proteins. Phosphorylation at serine residues 910 and 935 were shown tobe dependent on an active LRRK2 conformation and further, that LRRK2kinase inhibitors can inhibit phosphorylation at these two sites[Biochem J., 430, 405-13, 2010; J. Neurochem., 120:37-45, 2012].

LRRK2 kinase inhibitors have been shown to concentration-dependentlyinhibit LRRK2-Ser910 and LRRK2-Ser935 phosphorylation in cellular modelsexpressing LRRK2 and LRRK2-G2019S as well as human LRRK2-expressinglymphoblastoid cells from PD patients homozygous for the LRRK2 G2019Smutation. In addition, LRRK2 kinase inhibition dose-dependently inhibitsLRRK2-Ser910 and LRRK2-Ser935 phosphorylation in mouse brain after invivo administration of an LRRK2 inhibitor. [ACS Med. Chem. Lett. 3 (8),658-662, 2012.].

Common single nucleotide polymorphisms of LRRK2 have also beenassociated with Parkinson's disease [Nat Genet. 2009 December;41(12):1308-12] [Mov Disorder 27(6) 1823-1826 2012]. A recent genomewide association meta-analysis study where correction for G2019S carrierstatus was performed indicated that common LRRK2 variants with minorallele frequency (MAF) above 1% also are associated with an increasedrisk of Parkinson's disease [Lancet. 377, 641-649, 2011]. Further,investigations of common exonic polymorphic variants have highlightedseveral LRRK2 Parkinson's disease risk variants: in Caucasians theM1646T mutation, in the Asian population the A419V mutation and also thepreviously found G2385R mutation. Genome studies have also identifiedother LRRK2 Parkinson's disease risk variants such as N551K, R1398H,K1423K, R1441G, R1441H, R1441C, R1628P, S1647T, Y1699C, I2020T and Y2189[Lancet Neurol. 10, 898-908, 2011]. This indicates that LRRK2 inhibitorsalso could be useful as disease-modifying treatment in Parkinson'sdisease patients carrying common genomic LRRK2 variants such as M1646T,G2385R and A419V, in particular, but also common and rare LRRK2 variantssuch as N551K, R1398H, K1423K, R1441G, R1441H, R1441C, R1628P, S1647T,Y1699C, I2020T and Y2189C.

It has recently been demonstrated that the LRRK2 autophosphorylation onS1292 occurs in vivo and that it can be inhibited by LRRK2 kinaseinhibition. In addition, the S1292 phosphorylation is enhanced byseveral of the familial Parkinson Disease LRRK2 variants. Theautophosphorylation therefore serves as a valuable LRRK2 kinase activityindicator because familial Parkinson Disease LRRK2 variants increase thelevels of LRRK2 autophosphorylation on S1292. However, since theParkinson Disease variants increase the autophosphorylation, it hasfurther been suggested that the phosphorylation S1292 may be importantfor the abnormal effects of the kinase, and thus be an important riskfactor for Parkinson's disease [Science Trans. Med, Vol. 4, 164, 1-12,2012].

Indeed, as discussed above, as the clinical features of LRRK2 associatedand idiopathic Parkinson's disease are very similar this also suggeststhat LRRK2 inhibitors could be useful for the treatment of sporadic PD.

As established above, LRRK2 inhibitors may be used in the treatment ofParkinson's disease and particular mention is made of Parkinson'sdisease associated with mutations in LRRK2, such as Gly2019Ser.Moreover, LRRK2 inhibitors are also expected to be useful in thetreatment of other diseases which are associated with LRRK2. LRRK2 hasbeen identified as a core component in Lewy bodies and is thus expectedto be useful in the treatment of Lewy body dementia [Neuropathol. Appl.Neurobiol., 34, 272-283, 2008]. Expression of LRRK2 mRNA is highlyenriched in brain, lungs, kidney, spleen and blood suggesting thatfunctional impact of increased LRRK2 activity is likely to be mostrelevant in pathogenic and pathologic conditions associated with thoseregions. Support for that notion can be found in studies showing anincreased risk of non-skin cancer in LRRK2 Gly2019Ser mutation carriersand especially for renal and lung cancer [Mov. Disorder, 25, 2536-2541,2010]. Over-expression of LRRK2 by chromosomal amplification has alsobeen identified in papillary renal and thyroid carcinomas. Also, geneticassociation of LRRK2 has been reported to diseases in where aberrantresponses of the immune system are involved. This is the case forinflammatory bowel diseases such as Crohn's disease and ulcerativecolitis as well as for leprosy [Nat Genet. 42, 1118-1125, 2010; Inflamm.Bowel. Dis. 16, 557-558, 2010; N Engl. J Med. 361, 2609-2618, 2009;Inflamm. Bowel. Dis. doi: 10.1002/ibd.21651, 2011].

To the inventors knowledge no one has developed arylpyrrolopyridinederived compounds as LRRK2 inhibitors.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found certainarylpyrrolopyridine derivatives which are LRRK2 inhibitors. Accordingly,in one embodiment the invention provides a compound of formula A, below

wherein

-   R1 represents H or a NHR2 group,-   R2 represents H or a 5 or 6 membered heteroaromatic ring with 1 or    2N, which heteroaromatic ring is optionally substituted with 1 or 2    groups each independently selected from the group comprising CF₃,    halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkylamine or C₁-C₃ alkoxy    amine,-   R3 represents a 5 or 6 membered aromatic ring or a 5 or 6 membered    heteroaromatic ring with 1 or 2 heteroatoms(s) selected from S or N,    which aromatic ring or heteroaromatic ring is optionally substituted    with H, OH, 1 or 2 C₁-C₃ alkyl, 1 or 2 C₁-C₃ alkoxy or a    trifluoromethyl,-   L is absent or represents (CH₂)_(n), n=1 or 2,-   R4 represents H, NH₂ or a 5 or 6 membered heterocylic ring with 1 or    2 heteroatom(s) selected from N or O, which heterocyclic ring is    optionally substituted with 1 or 2C₁-C₃ alkyl, 1 or 2C₂-C₃ alkoxy, 1    or 2C₁-C₃ alkyl amine or 1 or 2C₂-C₃ alkoxy amine,-   and pharmaceutical acceptable salts thereof,-   with the proviso that the compound is not selected from-   4-Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-(3-Hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile or-   4-(2,4-Dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of the above formula A and pharmaceuticallyacceptable salts thereof together with a pharmaceutically acceptableexcipient.

In one embodiment, the invention provides compounds of the above formulaA and pharmaceutically acceptable salts thereof for use in therapy.

In one embodiment, the invention provides compounds of the above formulaA and pharmaceutically acceptable salts thereof for use in a method forthe treatment of a disease associated with LRRK2.

In one embodiment, the invention relates to the use of a compound of theabove formula A and pharmaceutically acceptable salts thereof in themanufacture of a medicament for use in the treatment of a diseaseassociated with LRRK2.

In one embodiment, the invention relates to a method for the treatmentof a disease associated with LRRK2, the method comprising theadministration of a therapeutically effective amount of a compound ofthe above formula A and pharmaceutically acceptable salts thereof to apatient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

According to an embodiment of the invention the compounds of formula Amay have an R2 group selected from H or a 5 or 6 membered heteroaromaticring with 1 or 2N, which heteroaromatic ring is optionally substitutedwith 1 or 2C₁-C₃ alkyl, 1 or 2C₁-C₃ alkoxy, 1 or 2C₁-C₃ alkylamine or 1or 2C₁-C₃ alkoxy amine.

According to another embodiment of the invention the compounds offormula A may have an R2 group selected from the followingheteroaromatic rings

optionally substituted with 1 or 2 groups each independently selectedfrom the group comprising CF₃, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃alkylamine or C₁-C₃ alkoxy amine. * denotes the attachment point.

R3 may according to an embodiment be selected from the group comprising

Furthermore the compounds of formula A may in some embodiments have an—R3-L-R4 selected from the group comprising

-   wherein R5 and R6 each independently represent H, C₁-C₃ alkyl or    C₁-C₃ alkoxy and-   L and R4 are each independently defined herein above for    formula A. * denotes the attachment point.

Furthermore, R4 may be represented by

-   * denotes the attachment point.

In specific embodiments according to the invention the compounds areselected from

-   4-(3-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-(3-Methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-(3-Ethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-(Thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-[4-(Morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-[1-(Morpholin-4-ylmethyl)pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-[3-Methyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-{4-[(Dimethylamino)methyl]-3-methylphenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-[3-Ethyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-[3-Methoxy-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   6-Amino-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   6-Amino-4-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   6-[(1-Methylpyrazol-3-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-(3-Methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-[3-Methyl-4-(morpholin-4-ylmethyl)phenyl]-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   6-[(1-Methylpyrazol-4-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,-   4-Phenyl-6-(pyridin-2-ylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-   6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-   6-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)amino]-4-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-   6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-   6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-   6-[(1-Methyl-1H-pyrazol-3-yl)amino]-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile,    or-   6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-   or pharmaceutical salt thereof.

The above mentioned compounds may be in a composition as the sole activeingredient or in combination with other active ingredients. Additionallyone or more pharmaceutically acceptable carriers or diluents may be inthe composition.

The compounds of the present invention may have one or more asymmetriccentres and it is intended that any optical isomers (i.e. enantiomers ordiastereomers) as separated, pure or partially purified optical isomersand any mixtures thereof including racemic mixtures, i.e. a mixture ofstereoisomers, are included within the scope of the invention.

In this context is understood that when specifying the enantiomericform, the compound is in enantiomeric excess, e.g. essentially in a pureform. Accordingly, one embodiment of the invention relates to a compoundof the invention having an enantiomeric excess of at least 60%, at least70%, at least 80%, at least 85%, at least 90%, at least 96%, preferablyat least 98%.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. The compounds of the present invention may alsobe resolved by the formation of diastereomeric derivatives. Additionalmethods for the resolution of optical isomers, known to those skilled inthe art, may be used. Such methods include those discussed by J. Jaques,A. Collet and S. Wilen in “Enantiomers, Racemates, and Resolutions”,John Wiley and Sons, New York (1981). Optically active compounds canalso be prepared from optically active starting materials.

Furthermore, when a double bond or a fully or partially saturated ringsystem is present in the molecule geometric isomers may be formed. It isintended that any geometric isomers as separated, pure or partiallypurified geometric isomers or mixtures thereof are included within thescope of the invention. Likewise, molecules having a bond withrestricted rotation may form geometric isomers. These are also intendedto be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

In the present context, “pharmaceutically acceptable salts” includepharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable metal salts, ammonium and alkylated ammonium salts. Acidaddition salts include salts of inorganic acids as well as organicacids.

Examples of suitable inorganic acids include hydrochloric, hydrobromic,hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.

Examples of suitable organic acids include formic, acetic,trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric,fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic,malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,p-toluenesulfonic acids, theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline and the like.Further examples of pharmaceutical acceptable inorganic or organic acidaddition salts include the pharmaceutically acceptable salts listed inJ. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.

The term “aromatic” refers to a cyclic moiety having a conjugatedunsaturated (4n+2)π electron system (where n is a positive integer),sometimes referred to as a delocalized π electron system. The term“heteroaromatic” intents to indicate an aromatic ring structure with oneor more heteroatoms. Examples may include pyridinyl and pyrimidinyl.

In the present context, “alkyl” is intended to indicate a straight orbranched saturated hydrocarbon. In particular, C₁₋₆-alkyl is intended toindicate such hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms andlikewise C₁₋₃-alkyl is intended to indicate a hydrocarbon having 1, 2 or3 carbon atoms. Typical alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,isopentyl, hexyl and the like.

The term “alkoxy” as used herein refers to a group of formula —O— alkyl,wherein alkyl is defined as above. In particular, C₁-C₆-akoxy isintended to indicate such hydrocarbon having 1, 2, 3, 4, 5 or 6 carbonatoms and likewise C₁-C₃-akoxy indicate is intended to indicate ahydrocarbon having 1, 2 or 3 carbon atoms. Examples of alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy, butoxy,isobtoxy, t-butoxy, pentoxy, isopropoxy and the like.

The term “alkylamine” or “alkoxyamine” is intended to refer to an aminein the form of RNH₂ wherein R is an alkyl or alkoxy group as definedhereinabove.

In the present context, “halogen” is intended to indicate members of the7^(th) main group of the periodic table of the elements, such as fluoro,chloro, bromo and iodo.

“Heteroatom” is intended to mean sulfur, oxygen or nitrogen.

The term “cyclic” as used herein refers to any cyclic structure,including alicyclic, heterocyclic, aromatic and heteroaromatic non-fusedring systems. The term “membered” is meant to denote the number ofskeletal atoms that constitute the ring. Thus, for example, pyridinyl,pyranyl, and pyrimidinyl are six-membered rings and pyrrolyl,tetrahydrofuranyl, and thiophenyl are five-membered rings.

The terms “heterocycle”, “heterocyclic” and “heterocyclyl” as usedherein, alone or in combination, refers to saturated or unsaturatednonaromatic rings containing from 5 to 6 ring atoms where one or more ofthe ring atoms are heteroatoms.

In some embodiments of the invention a heterocylic ring is intended tomean a 5 or 6 membered cyclic ring structure with 1 or 2 heteroatom(s).

The terms “substituents” or “substituted” as used herein, alone or incombination, refer to groups which may be used to replace hydrogen.

In the present context, the term “therapeutically effective amount” of acompound is intended to indicate an amount sufficient to cure, alleviateor partially arrest the clinical manifestations of a given disease andits complications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, e.g. by constructing a matrix of values andtesting different points in the matrix, which is all within the ordinaryskills of a trained physician.

In the present context, the term “treatment” and “treating” means themanagement and care of a patient for the purpose of combating a disease.The term is intended to include the full spectrum of treatments for agiven disease from which the patient is suffering, such asadministration of the active compound to alleviate the symptoms orcomplications, to delay the progression of the disease, to alleviate orrelief the symptoms and complications, and/or to cure or eliminate thedisease. The patient to be treated is preferably a mammal, in particulara human being. In the present context, “disease” can be used synonymouswith disorder, condition, malfunction, dysfunction and the like.

As established above, LRRK2 inhibitors may by used in the treatment ofParkinson's disease and particular mention is made of Parkinson'sdisease associated with mutations in LRRK2, such as Gly2019Ser.Moreover, LRRK2 inhibitors are also expected to be useful in thetreatment of other diseases which are associated with LRRK2. LRRK2 hasbeen identified as a core component in Lewy bodies and is thus expectedto be useful in the treatment of Lewy body dementia [Neuropathol. Appl.Neurobiol., 34, 272-283, 2008]. Expression of LRRK2 mRNA is highlyenriched in brain, lungs, kidney, spleen and blood suggesting thatfunctional impact of increased LRRK2 activity is likely to be mostrelevant in pathogenic and pathologic conditions associated with thoseregions. Support for that notion can be found in studies showing anincreased risk of non-skin cancer in LRRK2 Gly2019Ser mutation carriersand especially for renal and lung cancer [Mov. Disorder, 25, 2536-2541,2010]. Over-expression of LRRK2 by chromosomal amplification has alsobeen identified in papillary renal and thyroid carcinomas. Also, geneticassociation of LRRK2 has been reported for diseases where aberrantresponses of the immune system are involved. This is the case forinflammatory bowel diseases such as Crohn's disease and ulcerativecolitis as well as for leprosy [Nat Genet. 42, 1118-1125, 2010; Inflamm.Bowel. Dis. 16, 557-558, 2010; N Engl. J Med. 361, 2609-2618, 2009;Inflamm. Bowel. Dis. doi: 10.1002/ibd.21651, 2011].

Thus, the compounds, as outlined in formula A hereinabove, orcompositions comprising said compounds may be used in treatment of adisease or disorder characterised by over-expression of LRRK2 or amutated form of LRRK2 such as G2019S, I2020T, M1646T, G2385R, A419V,N551K, R1398H, K1423K, R1441G, R1441H, R1441C, R1628P, S1647T, Y1699C,I2020T or Y2189C.

The disease or disorder may be a CNS disease selected from Lewy bodydementia or Parkinson's disease, such as idiopathic Parkinson's diseaseor sporadic Parkinson's disease or in a Parkinson's disease patientcarrying any one of the above mentioned LRRK2 mutations, in particularthe G2019S mutation.

In a further embodiment, the compounds, as outlined in formula Ahereinabove, or compositions comprising said compounds may be used inthe treatment of cancer or an immune related disorder characterised byover-expression of LRRK2 or a mutated form of LRRK2 such as G2019S,I2020T, M1646T, G2385R, A419V, N551K, R1398H, K1423K, R1441G, R1441H,R1441C, R1628P, S1647T, Y1699C, I2020T or Y2189C.

The cancer diseases may reside in the brain, lungs, kidney and spleen orblood organs such as renal cancer, lung cancer, skin cancer, andpapillary renal and thyroid carcinomas.

The immune related disorder may in one embodiment be Crohn's disease,ulcerative colitis or leprosy.

In one embodiment, the compound of the present invention is administeredin an amount from about 0.001 mg/kg body weight to about 100 mg/kg bodyweight per day. In particular, daily dosages may be in the range of 0.01mg/kg body weight to about 50 mg/kg body weight per day. The exactdosages will depend upon the frequency and mode of administration, thesex, the age the weight, and the general condition of the subject to betreated, the nature and the severity of the condition to be treated, anyconcomitant diseases to be treated, the desired effect of the treatmentand other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 1-1000 mg/dayof a compound of the present invention, such as 1-500 mg/day.

The compounds of the present invention may be administered alone as apure compound or in combination with pharmaceutically acceptablecarriers or excipients, in either single or multiple doses. Thepharmaceutical compositions according to the invention may be formulatedwith pharmaceutically acceptable carriers or diluents as well as anyother known adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 22^(nd) Edition, Pharmaceutical Press, 2012. Inthe present context, “excipient”, “carrier”, “diluent”, “adjuvant” andthe like are used synonymously and are intended to mean the same.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragées, pills, lozenges, powders andgranules. Where appropriate, they can be prepared with coatings.

Liquid dosage forms for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use.

Other suitable administration forms include suppositories, sprays,ointments, creams, gels, inhalants, dermal patches, implants, etc.

Conveniently, the compounds of the invention are administered in a unitdosage form containing said compounds in an amount of about 0.1 to 500mg, such as 10 mg, 50 mg 100 mg, 150 mg, 200 mg or 250 mg of a compoundof the present invention.

For parenteral administration, solutions of the compound of theinvention in sterile aqueous solution, aqueous propylene glycol, aqueousvitamin E or sesame or peanut oil may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theaqueous solutions are particularly suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. Thesterile aqueous media employed are all readily available by standardtechniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions and various organic solvents.Examples of solid carriers are lactose, terra alba, sucrose,cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate,stearic acid and lower alkyl ethers of cellulose. Examples of liquidcarriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids,fatty acid amines, polyoxyethylene and water. The pharmaceuticalcompositions formed by combining the compound of the invention and thepharmaceutically acceptable carriers are then readily administered in avariety of dosage forms suitable for the disclosed routes ofadministration.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation maybe tablet, e.g. placed in a hard gelatine capsule in powder or pelletform or in the form of a troche or lozenge. The amount of solid carriermay vary but will usually be from about 25 mg to about 1 g.

If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

Tablets may be prepared by mixing the active ingredient with ordinaryadjuvants and/or diluents followed by compression of the mixture in aconventional tabletting machine. Examples of adjuvants or diluentscomprise corn starch, potato starch, talcum, magnesium stearate,gelatine, lactose, gums, and the like. Any other adjuvants or additivesusually used for such purposes such as colourings, flavourings,preservatives etc. may be used provided that they are compatible withthe active ingredients.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various “compounds” of the inventionor particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

Preparation of the Compounds of the Invention

The compounds of the present invention of the general formula A hereinabove wherein R1 to R4 and L are as defined above can be prepared by themethods outlined in the following reaction schemes and examples. In thedescribed methods it is possible to make use of variants ormodifications, which are themselves known to chemists skilled in the artor could be apparent to the person of ordinary skill in this art.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person skilled in the art in light of thefollowing reaction schemes and examples.

The products of the invention can be prepared by the following generalmethods:

Compounds of formula I or salts thereof with R3 being a 5 or 6 memberedaromatic ring or a 5 or 6 membered heteroaromatic ring with 1 or 2heteroatoms(s) selected from S or N, which aromatic ring orheteroaromatic ring is optionally substituted with H, OH, 1 or 2C₁-C₃alkyl, 1 or 2C1-C3 alkoxy or trifluoromethyl; L is absent or representsCH_(n), n=1 or 2; R4 represents H, NH₂ or a 5 or 6 membered heterocyclicring with 1 or 2 heteroatoms(s) selected from N or O, which heterocyclicring is optionally substituted with C1-C3 alkyl, C2-C3 oxy, C1-C3 alkylamine or C2-C3 alkoxy amine, may be prepared by the followingprocedures.

-   -   a) Reacting a compound of formula II by means of a        cross-coupling reaction, such as a Suzuki coupling or other        transition metal-catalysed cross-coupling reactions as described        in (D. W. Knight, “Coupling Reactions Between sp2 Carbon        Centres” in Comprehensive Organic Synthesis, Vol. 3, pp.        481-520, Pergamon Press, 1991), with a boronic acid (R3B(OH)₂)

-   -   -   or a corresponding boronic acid ester, where R3 represents            for example 3-methoxyphenyl, in a suitable solvent such as a            mixture of 1,4-dioxane and water in the presence of a            suitable catalyst such as            bis(tri-tert-butylphosphine)palladium(0) and a suitable base            such as potassium fluoride at a suitable temperature from            60-150° C. The heating could be performed in a microwave            system.

    -   b) Step 1: Attachment of a protecting group (P) such as        phenylsulfonyl to a compound of formula II utilising standard        chemical transformations known to a person skilled in the art,        such as reacting formula II with phenylsulfonyl chloride in a        suitable solvent such as dichloromethane, in the presence of a        base such as triethylamine and a catalyst such as        4-dimethylaminopyridine at an appropriate temperature such as        ambient temperature to give a compound of formula III.

    -   Step 2: Reacting a compound of formula III by means of a        cross-coupling reaction, such as Suzuki coupling, or other        transition metal-catalysed cross-coupling reaction, with an        optionally protected boronic acid (R3B(OH)₂) or a corresponding        boronic acid ester, such as        1-(triisopropylsilyl)pyrrol-3-ylboronic acid, in a suitable        solvent such as a mixture of tetrahydrofuran and water in the        presence of a suitable catalyst such as        [1,1′-bis(di-tert-butylphosphino)-ferrocene]palladium(II)        dichloride and a suitable base such as potassium carbonate at a        suitable temperature from 60-150° C. The heating could be        performed in a microwave system.

    -   Step 3: Reacting a compound of formula IV with aqueous        formaldehyde solution in a solvent such as ethanol, followed by        an amine such as morpholine, and heating at a suitable        temperature from 60-150° C. The heating could be performed in a        microwave system.

    -   Step 4: Removal of a protecting group from a compound of formula        V, using standard chemical transformations known to a person        skilled in the art. This includes hydrolysis of a compound of        formula V where P is phenylsulfonyl, in a mixture of water and        another suitable solvent such as tetrahydrofuran, in the        presence of a catalyst such as potassium carbonate at a suitable        temperature from 60-150° C. The heating could be performed in a        microwave system.

-   -   c) Step 5: Reacting a compound of formula III as prepared in        step 1 above by means of a cross-coupling reaction, such as        Suzuki coupling, or other transition metal-catalysed        cross-coupling reaction, with an optionally-substituted        formyl-substituted boronic acid (R3B(OH)₂) or a corresponding        boronic acid ester, such as 4-formyl-3-methylphenylboronic acid,        in a suitable solvent such as a mixture of tetrahydrofuran and        water in the presence of a suitable catalyst such as        [1,1′-bis(di-tert-butylphosphino)-ferrocene]palladium(II)        dichloride and a suitable base such as potassium carbonate at a        suitable temperature from 60-150° C. The heating could be        performed in a microwave system.    -   Step 6: Reacting a compound of formula VI with an amine such as        morpholine, in a suitable solvent such as dichloromethane and a        catalyst such as acetic acid, followed by a reducing agent such        as sodium triacetoxyborohydride and heating at a suitable        temperature such as ambient.    -   Step 7: Removal of a protecting group from a compound of formula        V, using standard chemical transformations known to a person        skilled in the art. This includes hydrolysis of a compound of        formula V where P is phenylsulfonyl in a mixture of water and        another suitable solvent such as tetrahydrofuran, in the        presence of a catalyst such as potassium carbonate at a suitable        temperature from 60-150° C. The heating could be performed in a        microwave system.

Compounds of formula X or salts thereof with R3 being a 5 or 6 memberedaromatic ring or a 5 or 6 membered heteroaromatic ring with 1 or 2heteroatoms(s) selected from S or N; L is CH₂, R4 represents NH₂, NMe₂or a 5 or 6 membered heterocyclic ring with 1 or 2 heteroatoms(s)selected from N and/or O, which heterocyclic ring is optionallysubstituted with C1-C3 alkyl, C2-C3 oxy, C1-C3 alkyl amine or C2-C3alkoxy amine; R5 represents H or C1-C3 alkyl, may be prepared by thefollowing procedures.

Step 8: Reacting a compound of formula III as prepared above by means ofa cross-coupling reaction, such as Suzuki coupling, or other transitionmetal-catalysed cross-coupling reaction, with an X—,formyl-disubstituted aryl boronic acid (XHCOR3B(OH)2) (X═Cl, Br or I) ora corresponding boronic acid ester, such as3-chloro-4-formyl-3-phenylboronic acid, in a suitable solvent such as amixture of tetrahydrofuran and water in the presence of a suitablecatalyst such as[1,1′-bis(di-tert-butylphosphino)-ferrocene]palladium(II) dichloride anda suitable base such as potassium carbonate at a suitable temperaturefrom 60-150° C. The heating could be performed in a microwave system.

Step 9: Reacting a compound of formula VII by means of a cross-couplingreaction such as a Heck reaction, or other transition metal catalysedcross-coupling reaction with an vinyl boroxane (R5CH:CHBO)₃, such as2,4,6-trivinylcyclotriboroxane-pyridine complex, in the presence of asuitable catalyst such as tetrakis(triphenylphosphine)palladium(0) witha suitable base such as potassium carbonate, in a suitable solventmixture such as 1,2-dimethoxyethane and water, and an appropriatetemperature from 60-180° C. The heating could be performed in amicrowave system.

Step 10: Reacting a compound of formula VIII with an amine such asmorpholine, in a suitable solvent such as dichloromethane and a catalystsuch as acetic acid, followed by a reducing agent such as sodiumtriacetoxyborohydride and heating at a suitable temperature such asambient.

Step 11: Reacting a compound of formula IX with hydrogen gas at anappropriate pressure such as ambient in a suitable solvent such asmethanol, in the presence of a catalyst such as 10% palladium on carbon

Compounds of formula XIII or salts thereof with R3 being a 5 or 6membered aromatic ring or a 5 or 6 membered heteroaromatic ring with 1or 2 heteroatoms(s) selected from S or N, which aromatic ring orheteroaromatic ring is optionally substituted with H, OH, 1 or 2C₁-C₃alkyl, 1 or 2C1-C3 alkoxy or trifluoromethyl, may be prepared by thefollowing procedures.

a) Step 12: Reacting a compound of formula II with an oxidising agentsuch as meta-chloroperoxybenzoic acid in a suitable solvent such aschloroform, at an appropriate temperature such as −20° C. to ambient,over a suitable time such as 16 hours, followed by treatment withmethanesulfonic acid.

Step 13: Reacting a suspension of the methanesulfonic acid salt of acompound of formula XI in a suitable solvent such as acetonitrile withdimethyl sulphate, heating at a suitable temperature such as 40-70° C.and subsequent treatment with concentrated ammonia in methanol andheating in a sealed tube at an appropriate temperature such as 40-70° C.

Step 14: Reacting a compound of formula XII by means of a cross-couplingreaction, such as Suzuki coupling, or other transition metal-catalysedcross-coupling reactions as described in [D. W. Knight, “CouplingReactions Between sp2 Carbon Centres” in Comprehensive OrganicSynthesis, v. 3, pp. 481-520, Pergamon Press, 1991, with a boronic acid(R3B(OH)₂) or a corresponding boronic acid ester, where R3 representsfor example phenyl, in a suitable solvent such as a mixture of1,4-dioxane and water in the presence of a suitable catalyst such asbis(tri-tert-butylphosphine)palladium(0) and a suitable base such aspotassium fluoride at a suitable temperature from 60-150° C. The heatingcould be performed in a microwave system.

b) Step 15: Reacting the methanesulfonic acid salt of a compound offormula XI as prepared above in an appropriate solvent such as dimethylformamide with methanesulfonyl chloride, and heating at a suitabletemperature of 60-100° C.

Step 16: Attachment of a protecting group (P) such as phenylsulfonyl toa compound of formula XIV utilising standard chemical transformationsknown to a person skilled in the art, such as reacting formula XIV withphenylsulfonyl chloride in a suitable solvent such as dichloromethane,in the presence of a base such as triethylamine and a catalyst such as4-dimethylaminopyridine at an appropriate temperature such as ambienttemperature to give a compound of formula XV.

Step 17: Reacting a compound of formula XV by means of a cross-couplingreaction, such as Buchwald coupling, or other transition metal-catalysedcross-coupling reactions, with a benzylic amine (RCH₂NH₂) where Rrepresents for example phenyl, in a suitable solvent such as a dimethylformamide in the presence of a suitable catalyst such astris(dibenzylidineacetone)dipalladium(0), phosphine ligand such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and a suitable base suchas sodium tert-butoxide at a suitable temperature from 60-150° C. Theheating could be performed in a microwave system.

Step 18: Reacting a compound of formula XVI by means of a cross-couplingreaction, such as Suzuki coupling, or other transition metal-catalysedcross-coupling reactions as with a boronic acid (R3B(OH)₂) or acorresponding boronic acid ester, where R3 represents for example3-methylphenylboronic acid, in a suitable solvent such as a mixture of1,4-dioxane and water in the presence of a suitable catalyst such asbis(tri-tert-butylphosphine)palladium(0) and a suitable base such aspotassium fluoride at a suitable temperature from 60-150° C. The heatingcould be performed in a microwave system.

Step 19: Reaction of a compound of formula XVII in a suitable solventsuch as ethanol with hydrogen gas at a suitable temperature and pressuresuch as ambient, in the presence of a catalyst such as 10% palladium oncarbon.

Compounds of formula XIX or salts thereof with R2 representing a 5 or 6membered heteroaromatic ring with 1 or 2N, which heteroaromatic ring isoptionally substituted with C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, halo, C₁-C₃alkoxy, C₁-C₃ alkylamine or C₁-C₃ alkoxy amine, R3 being a 5 or 6membered aromatic ring or a 5 or 6 membered heteroaromatic ring with 1or 2 heteroatoms(s) selected from S or N, which aromatic ring orheteroaromatic ring is optionally substituted with H, OH, 1 or 2C₁-C₃alkyl, 1 or 2C1-C3 alkoxy or trifluoromethyl, may be prepared by thefollowing procedures.

a) Step 20: Reacting a compound of formula XIV as prepared above bymeans of a cross-coupling reaction, such as Buchwald coupling, or othertransition metal-catalysed cross-coupling reactions, with an amine(R2NH₂) where R2 represents for example (1-methyl-1H-pyrazol-3-yl), in asuitable solvent such as a dimethyl formamide in the presence of asuitable catalyst such as tris(dibenzylidineacetone)dipalladium(0), anappropriate phosphine ligand such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and a suitable base suchas sodium tert-butoxide at a suitable temperature from 60-150° C. Theheating could be performed in a microwave system.

Step 21: Reacting a compound of formula XVIII by means of across-coupling reaction, such as Suzuki coupling, or other transitionmetal-catalysed cross-coupling reactions as with a boronic acid(R3B(OH)₂) or a corresponding boronic acid ester, where R3 representsfor example phenyl, in a suitable solvent such as a mixture of1,4-dioxane and water in the presence of a suitable catalyst such asbis(tri-tert-butylphosphine)palladium(0) and a suitable base such aspotassium fluoride at a suitable temperature from 60-150° C. The heatingcould be performed in a microwave system.

b) Step 22: Reacting a compound of formula XIV with sodium iodide andacetyl chloride in a suitable solvent such as acetonitrile and at anappropriate temperature from ambient to 80° C., to give a compound offormula XX.

Step 23: Attachment of a protecting group (P) such as2-(trimethylsilyl)ethoxy]methyl (SEM) to a compound of formula XXutilising standard chemical transformations known to a person skilled inthe art, such as reacting formula XX with 2-(trimethylsilyl)ethoxymethylchloride in a suitable solvent such as dimethyl formamide, in thepresence of a base such as sodium hydride at an appropriate temperaturefrom −20° C. to ambient, to give a compound of formula XXI.

Step 24: Reacting a compound of formula XXI by means of a cross-couplingreaction, such as Stille coupling, or other transition metal-catalysedcross-coupling reaction, with an optionally substitutedtri-n-butylstannane (R3Sn(Bu)₃), such as4-methyl-2-(tributylstannyl)pyridine, in a suitable solvent such as1,4-dioxane, in the presence of a catalyst such astetrakis(triphenylphosphine)palladium(0) and copper iodide in thepresence of lithium chloride, at a suitable temperature from 60-150° C.The heating could be performed in a microwave system.

Step 25: Reacting a compound of formula XXII by means of across-coupling reaction, such as Buchwald coupling, or other transitionmetal catalyzed cross-coupling reactions, with an aryl amine R2NH₂, in asuitable solvent such as toluene in the presence of a suitable catalystsuch as tris(dibenzylideneacetone)dipalladium(0), phosphine ligand suchas 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and asuitable base such as sodium tert-butoxide at a suitable temperaturefrom 60-150° C. The heating could be performed in a microwave system.

Step 26: Removal of a protecting group from a compound of formula XXIII,using standard chemical transformations known to a person skilled in theart, such as reacting with tetra-n-butylammonium fluoride in a suitablesolvent such as tetrahydrofuran at an appropriate temperature from0-100° C., to give a compound of formula XIX

c) Step 27: Reacting a compound of formula XX by means of across-coupling reaction as described above, to give a compound offormula XXIV.

Step 28: Attachment of a protecting group (P) such as2-(trimethylsilyl)ethoxy]methyl (SEM) to a compound of formula XXIV asdescribed above, to give a compound of formula XXII, which can betransformed to compounds of formula XIX as described above.

Compounds of formula XXVI or salts thereof with R2 representing a 5 or 6membered heteroaromatic ring with 1 or 2N, which heteroaromatic ring isoptionally substituted with C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkylamineor C₁-C₃ alkoxy amine, with R3 being a 5 or 6 membered aromatic ring ora 5 or 6 membered heteroaromatic ring with 1 or 2 heteroatoms(s)selected from S or N, which aromatic ring or heteroaromatic ring isoptionally substituted with H, OH, 1 or 2C₁-C₃ alkyl, 1 or 2C₁-C₃ alkoxyor trifluoromethyl, L represents CH_(n) (n=1 or 2), and R4 represents H,NH₂ or a 5 or 6 membered heterocyclic ring with 1 or heteroatom(s)selected from N or O, which heterocyclic ring is optionally substitutedwith C₁-C₃ alkyl, C₂-C₃ alkoxy, C₁-C₃ alkylamine or C₂-C₃ alkoxy amine,may be prepared by the following procedures.

Step 29: Reacting a compound of formula XVIII as prepared above by meansof a cross-coupling reaction, such as Suzuki coupling, or othertransition metal-catalysed cross-coupling reactions with aformyl-substituted boronic acid (HCO—R3B(OH)2) or a correspondingboronic acid ester, where R3 represents for example phenyl, in asuitable solvent such as a mixture of 1,4-dioxane and water in thepresence of a suitable catalyst such asbis(tri-tert-butylphosphine)palladium(0) and a suitable base such aspotassium fluoride at a suitable temperature from 60-150° C. The heatingcould be performed in a microwave system.

Step 30: Reacting a compound of formula XXV with an amine such asmorpholine, in a suitable solvent such as dichloromethane and a catalystsuch as acetic acid, followed by a reducing agent such as sodiumtriacetoxyborohydride and heating at a suitable temperature such asambient.

General Methods

Microwave heating was performed with a CEM Discover® instrument.

The compounds of the present invention were characterised by highperformance liquid chromatography-mass spectroscopy (LC-MS) using one ofMethods A-F, and proton nuclear magnetic resonance (¹H NMR)spectroscopy.

LC-MS Method A

-   Instruments: Agilent HP1100 with DAD and MSD G1946 D (positive and    negative ionisation, scanning range: 150-1000 Da) or Agilent HP1200    with DAD and MSD 6140 (positive and negative ionisation, scanning    range: 150-1000 Da). UV detection was at 230 nm, 254 nm and 270 nm.    The conditions and methods are identical for both instruments.-   Column: Gemini NX 5 μm C18, 30×2.1 mm, from Phenomenex. Temperature:    40° C.-   Mobile phase: Solvent A: Water/10 mM ammonium formate/0.08% (v/v)    formic acid pH=3.5.    -   Solvent B: Acetonitrile/5.3% (v/v) Solvent A/0.08% (v/v) formic        acid.    -   Injection volume: 1 μL

Gradient:

Flow Rate Time (min) Solvent A (%) Solvent B (%) (ml min⁻¹) 0.00 95 5 10.25 95 5 1 2.5 5 95 1 2.55 5 95 1.7 3.60 5 95 1.7 3.65 5 95 1 3.70 95 51 3.75 95 5 1

LC-MS Method B

-   Instrument: Agilent 1200 SL series connected to an Agilent MSD 6140    single quadrupole with a multimode source (ESI/APCI, positive and    negative mode ionisation, scanning range 150-850 Da). UV detection    was at 230 nm, 254 nm and 270 nm.-   Column: Kinetex C18, 2.6 microns, 50×2 mm, from Phenomenex.    Temperature: 55° C.-   Mobile phase: Solvent A: Water/10 mM ammonium formate/0.08% (v/v)    formic acid pH=3.5.    -   Solvent B: Acetonitrile/5.3% (v/v) Solvent A/0.08% (v/v) formic        acid.    -   Injection volume: 1 μL.

Gradient:

Time Solvent A Flow Rate (min) (%) Solvent B (%) (ml min⁻¹) 0.00 95 51.3 0.12 95 5 1.3 1.30 5 95 1.3 1.35 5 95 1.6 1.85 5 95 1.6 1.90 5 951.3 1.95 95 5 1.3

LC-MS Method C

-   Column: BEH C18, 1.7 microns, 50×2.1 mm from Acquity Temperature:    55° C.-   Mobile phase: Solvent A: Water/0.1% (v/v) formic acid.    -   Solvent B: Acetonitrile/0.1% (v/v) formic acid.-   Gradient:

Time Solvent A Flow Rate (min) (%) Solvent B (%) (ml min⁻¹) 0.00 97 30.6 0.40 97 3 0.6 3.2 2 98 0.6 3.8 2 98 0.6 4.2 97 3 0.6 4.5 97 3 0.6

LC-MS Method D

-   Column: BEH C18, 1.7 microns, 50×2.1 mm from Acquity Temperature:    55° C.-   Mobile phase: Solvent A: Water/0.1% (v/v) formic acid.    -   Solvent B: Acetonitrile/0.1% (v/v) formic acid.

Gradient:

Time Solvent A Flow Rate (min) (%) Solvent B (%) (ml min⁻¹) 0.00 97 30.4 0.50 97 3 0.4 1.5 10 90 0.4 1.8 10 90 0.4 2.2 5 95 0.4 3.2 5 95 0.44.0 97 3 0.4

LC-MS Method E

-   Column: XBridge C18, 2.5 microns, 50×4.6 mm Temperature: 35° C.-   Mobile phase: Solvent A: Water/0.1% (v/v) formic acid.    -   Solvent B: Acetonitrile/0.1% (v/v) formic acid.-   Gradient:

Time Solvent A Solvent B Flow Rate (min) (%) (%) (ml min⁻¹) 0.00 95 51.3 0.50 95 5 1.3 1.0 85 15 1.3 3.3 2 98 1.3 5.2 2 98 1.3 5.5 95 5 1.36.0 95 5 1.3

LC-MS Method F

-   Column: XBridge C18, 2.5 microns, 50×4.6 mm Temperature: 35° C.-   Mobile phase: Solvent A: 5 mM Ammonium bicarbonate in water (pH 10)    -   Solvent B: Acetonitrile-   Gradient:

Time Solvent A Flow Rate (min) (%) Solvent B (%) (ml min⁻¹) 0.00 95 51.3 0.50 95 5 1.3 1.0 85 15 1.3 3.3 2 98 1.3 5.2 2 98 1.3 5.5 95 5 1.36.0 95 5 1.3

¹H (400 MHz) nuclear magnetic resonance (NMR) analyses were performedusing a Bruker DPX-400 MHz NMR spectrometer. The spectral reference wasthe known chemical shift of the sample solvent. ¹H NMR data are reportedindicating the chemical shift (δ) as parts per million (ppm), theintegration (e.g. 1H), and the multiplicity (s, singlet; d, doublet; t,triplet; q, quartet; sept, septet; m, multiplet; br, broad; dd, doubletof doublets, etc.).

Preparation of Intermediates

1-(Benzenesulfonyl)-4-chloro-1H-pyrollo[2,3-b]pyridine-3-carbonitrile

4-Chloro-1H-pyrollo-[2,3-b]pyridine-3-carbonitrile (3.61 g) was taken upin dichloromethane (120 mL) in a dry round bottomed flask.4-Dimethylaminopyridine (0.25 g) was added, followed by triethylamine(4.24 mL). Phenylsulfonyl chloride (3.11 ml) was then added, and thereaction was stirred at ambient temperature under nitrogen for 3.5hours. The reaction mixture was then partitioned between dichloromethane(200 mL) and brine (100 ml). The organic phase was separated, dried overmagnesium sulphate and concentrated in vacuo. The residue was trituratedfrom diethyl ether (2×50 mL). The resulting precipitate was filtered anddried under suction to furnish 6.33 g (98%) of a beige solid, identifiedas1-(benzenesulfonyl)-4-chloro-1H-pyrollo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 318 (MH⁺); t_(R)=2.59.

1-(Benzenesulfonyl)-4-(1H-pyrrol-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

1-(Benzenesulfonyl)-4-chloro-1H-pyrollo[2,3-b]pyridine-3-carbonitrile(0.20 g) was taken up in tetrahydrofuran (4 mL).1-(Triisopropylsilyl)pyrrol-3-ylboronic acid (0.20 g) was added,followed by water (1 mL) and potassium carbonate (0.26 g). The reactionwas degassed with nitrogen and[1,1′-bis(di-tert-butylphosphino)-ferrocene]palladium(II) dichloride(0.020 g) was added and the reaction was further degassed and heated to100° C. for 1 hour in a sealed microwave process vial. A further 0.10 gof 1-(triisopropylsilyl)pyrrol-3-ylboronic acid was added, followed by[1,1′-bis(di-tert-butylphosphino)-ferrocene]palladium(II) dichloride(0.010 g). The reaction was degassed with nitrogen and heated withmicrowaves at 100° C. for a further 1 hour. The reaction mixture wasthen cooled, and partitioned between ethyl acetate (50 mL) and brine (30mL). The separated organic phase was dried over magnesium sulphate andconcentrated in vacuo. The residue was then subjected to silica gel (20g) column chromatography (hexane to ethyl acetate/hexane (1:1) undergradient elution). The eluted material, obtained as an orange solid(0.087 g, 40%) was identified as1-(benzenesulfonyl)-4-(1H-pyrrol-3-yl)-H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 349 (MH⁺); t_(R)=2.5.

1-(Benzenesulfonyl)-4-[1-(morpholin-4-ylmethyl)-1H-pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

1-(Benzenesulfonyl)-4-(1H-pyrrol-3-yl)-H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.083 g) was taken up in ethanol (10 mL) and formaldehyde (37% aqueoussolution, 0.07 mL) was added, followed by morpholine (0.17 mL). Thereaction mixture was heated to 110° C. for 2 hours in a microwaveprocess vial. The reaction mixture was then cooled, and concentrated invacuo. The residue was partitioned between ethyl acetate (50 mL) andbrine (30 mL). The separated organic phase was dried over magnesiumsulphate and concentrated in vacuo. The residue was then subjected tosilica gel (10 g) column chromatography [dichloromethane then ethylacetate/dichloromethane (1:2) under gradient elution]. The elutedmaterial, obtained as a clear gum (0.029 g, 27%) was identified as1-(benzenesulfonyl)-4-[1-(morpholin-4-ylmethyl)pyrrol-3-yl]pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (m/z) (Method A) 448 (MH⁺); t_(R)=2.5.

1-(Benzenesulfonyl)-4-(4-formyl-3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

1-(Benzenesulfonyl)-4-chloro-1H-pyrollo[2,3-b]pyridine-3-carbonitrile(0.40 g) was taken up in tetrahydrofuran (12 mL).4-Formyl-3-methylphenylboronic acid (0.291 g) was then added, followedby water (3 mL) and potassium carbonate (0.52 g). The reaction mixturewas degassed with nitrogen and[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride(0.04 g) was added. The reaction mixture was then further degassed withnitrogen and heated to 100° C. for 1 hour in a sealed microwave processvial. The cooled reaction mixture was then partitioned between ethylacetate (150 mL) and brine (100 mL). The separated organic phase wasdried over magnesium sulphate and concentrated in vacuo. The residue wasthen loaded onto a 50 g silica gel column and eluted with hexane thenethyl acetate/hexane (1:2) (gradient elution). The eluted material,obtained as a yellow oil (0.38 g, 75%), was identified as1-(benzenesulfonyl)-4-(4-formyl-3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (m/z) (Method A) 402 (MH⁺); t_(R)=2.68.

1-(Benzenesulfonyl)-4-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrollo[2,3-b]pyridine-3-carbonitrile

1-(Benzenesulfonyl)-4-(4-formyl-3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.38 g) and morpholine (0.41 mL) were taken up in dichloroethane (20mL). Two drops of acetic acid were added to the resulting solution,followed by sodium triacetoxyborohydride (0.60 g). The reaction mixturewas stirred at ambient temperature under nitrogen for 24 hours and thenpartitioned between dichloromethane (150 mL) and brine (100 mL). Theorganic phase was separated, dried over magnesium sulphate andconcentrated in vacuo. The residue was then loaded onto a 50 g silicacolumn and eluted on a gradient from dichloromethane to 1:2 ethylacetate/dichloromethane to furnish a clear gum (0.40 g, 88%) identifiedas1-(benzenesulfonyl)-4-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrollo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 473 (MH⁺); t_(R)=2.22.

1-(Benzenesulfonyl)-4-(3-chloro-4-formylphenyl)-1H-pyrollo[2,3-b]pyridine-3-carbonitrile

The title compound was prepared analogously from Suzuki coupling with1-(benzenesulfonyl)-4-chloro-1H-pyrollo[2,3-b]pyridine-3-carbonitrileand 3-chloro-4-formylphenylboronic acid to furnish a white solid. Yield:187 mg, 28%. LC-MS (Method A) (m/z) 422 (MH⁺); t_(R)=2.7.

4-(3-Ethenyl-4-formylphenyl)-1H-pyrollo[2,3-b]pyridine-3-carbonitrile

1-(Benzenesulfonyl)-4-(3-chloro-4-formylphenyl)-1H-pyrollo[2,3-b]pyridine-3-carbonitrile(0.19 g) was taken up in 1,2-dimethoxylethane (7.5 mL) and2,4,6-trivinylcyclotriboroxane-pyridine complex (0.21 g) was added,followed by potassium carbonate (0.12 g), water (2.5 mL) andtetrakis(triphenylphosphine)palladium(0) (0.025 g). The reaction mixturewas degassed with nitrogen and then heated to 180° C. for 2 hours in asealed microwave process vial. The cooled reaction mixture was thenpartitioned between ethyl acetate (100 mL) and brine (60 mL). Theorganic phase was separated, dried over magnesium sulphate andconcentrated in vacuo. The reaction mixture was then triturated withacetonitrile, and the resulting precipitate filtered and dried undersuction to furnish 0.062 g (51%) of a yellow solid, identified as4-(3-ethenyl-4-formylphenyl)-1H-pyrollo[2,3-b]pyridine-3-carbonitrile.LC-MS (m/z) (Method A) 274 (MH⁺); t_(R)=2.25.

4-[3-Ethenyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrollo[2,3-b]pyridine-3-carbonitrile

The title compound was prepared by analogy with Example 7 via reductiveamination on4-(3-ethenyl-4-formylphenyl)-1H-pyrollo[2,3-b]pyridine-3-carbonitrilewith morpholine, to afford a white solid. Yield: 32 mg, 41%. LC-MS(Method A) (m/z) 345 (MH⁺); t_(R)=1.8

4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-7-oxidemethanesulfonic acid salt

4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (3.00 g) was suspendedin chloroform (60 mL) and the reaction mixture cooled to 0° C.meta-Chloroperoxybenzoic acid was then added portion-wise over 10 minand the reaction mixture was then stirred at ambient temperature for 16h. Methanesulfonic acid (1.64 mL) was then added drop wise over ˜1minute. The reaction mixture was then diluted with diethyl ether (60ml), cooled (ice-water bath) and then stirred for 30 minutes. Theresulting precipitate was filtered, and the residue was washed withdiethyl ether (3×20 mL). The resulting solid was dried in vacuo (60° C.)for 2 h to give 5.23 g (88%) of a beige solid, identified as4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-7-oxidemethanesulfonic acid salt; LC-MS (Method A) (m/z) 194 (MH+); tR=1.37.

6-Amino-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-7-oxidemethanesulfonic acid salt (2.00 g) was suspended in acetonitrile (15mL), and dimethyl sulfate (0.79 g) was then added. The suspension wasstirred at 60° C. for 16 h, after which a clear-brown solution wasformed.

The reaction mixture was cooled to room temperature and transferred into3×15 mL Ace glass tubes. 7N Ammonia in methanol (5 mL) was then added toeach tube. The sealed tubes were then heated at 70° C. for 48 h. Thereaction mixture was then cooled in an ice bath, the contents of eachtube combined and concentrated under reduced pressure. The residue waspurified by silica-gel flash chromatography [ethyl acetate in isohexane(0-100%), gradient elution]. The eluted material, obtained as anoff-white solid 0.053 g (5%), was identified as6-amino-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS (MethodA) (m/z) 193 (MH+); tR=1.79.

4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile-7-oxidemethanesulfonic acid (5.37 g) was suspended in DMF (50 mL).Methanesulphonyl chloride (10.87 g) was then added, and the reactionmixture was then heated to 80° C. for 10 min, resulting in a pale-brownsolution.

The reaction mixture was then cooled and evaporated under reducedpressure. The resulting yellow gum was triturated with dichloromethane.The precipitate was filtered and then dried to afford a light yellowpowder (2.72 g, 46%), identified as4,6-dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS (Method A)(m/z) 210 (M−H)⁻; tR=1.77.

1-(Benzenesulfonyl)-4,6-dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile was suspended inanhydrous dichloromethane (20 mL). Triethylamine (0.290 g) was thenadded, followed by 4-dimethylaminopyridine (0.023 g). To the reactionmixture was added benzensulfonyl chloride (0.41 g) drop-wise; a clearsolution was formed. The reaction mixture was left to stir at rt underN₂ for 2 h, and then evaporated under reduced pressure. The residue wastriturated with water; the resulting precipitate was filtered and driedat 60° C. in vacuo to a beige solid (0.56 g, 83%), identified as1-(benzenesulfonyl)-4,6-dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 352 (M+); tR=2.74.

6-(Benzylamino)-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

1-(Benzenesulfonyl)-4,6-dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.30 g), benzylamine (0.046 g), sodium tert-butoxide (0.40 g),tris(dibenzylideneacetone)dipalladium(0) (0.039 g) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.054 g)added to a microwave vial followed by dry DMF (15 mL). The mixture wasflushed with N₂ for ˜10 min, and then heated to 120° C. with microwavesfor 1 h in a sealed process vial. The reaction mixture was evaporated,and then subjected to silica-gel column chromatography [ethylacetate-isohexane (0-100%), gradient elution]. The eluted material,obtained as a red solid 0.14 g (59%), was identified as6-(benzylamino)-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS(Method A) (m/z) 283 (M+H+); tR=2.47.

6-(Benzylamino)-4-(3-methylphenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-(Benzylamino)-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.063g), 3-methylphenylboronic acid (0.040 g), potassium fluoride (0.026 g)and bis(tri-tert-butylphosphine)palladium (0) (0.006 g) were suspendedin 1,4-dioxane:water (6:1, 3.5 mL). The reaction mixture was thenstirred at room temperature under a stream of nitrogen for 5 min, andthen heated at 120° C. for 60 min in a sealed microwave process vial.After cooling to room temperature, the reaction mixture was diluted withethyl acetate (20 mL) and water (20 mL), and filtered through Celite.The organic phase was separated, and the aqueous layer was extractedwith ethyl acetate (3×20 mL). The combined organic extracts were washedwith brine (20 mL), dried over magnesium sulfate and concentrated invacuo. The residue was subjected to silica-gel flash chromatography[ethyl acetate-isohexane (0-100%), gradient elution]. The elutedmaterial, obtained as a beige solid (0.033 g, 58%), was identified as6-(benzylamino)-4-(3-methylphenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 339 (MH+); tR=2.65.

4-Chloro-6-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.118 g),1-methyl-1H-pyrazol-3-amine (0.027 g), sodium tert-butoxide (0.269 g),tris(dibenzylideneacetone)dipalladium(0) (0.026 g) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.035 g) wereadded to a microwave vial, followed by dry DMF (5 mL). The reactionmixture was flushed with N₂ for ˜10 min, and then heated to 80° C. withmicrowaves for 1 h. The reaction mixture was subjected to silica-gelflash column chromatography [dichloromethane-methanol (2-3%)]. Theeluted material, obtained as a yellow solid (0.055 g, 78%) wasidentified as4-chloro-6-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 273 (M+H+); tR=2.11.

4-(4-Formyl-3-methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-Chloro-6-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.030 g), 3-methyl-4-formylphenylboronic acid (0.036 g), potassiumfluoride (0.019 g) and bis(tri-tert-butylphosphine)palladium(0) (0.008g) were suspended in 1,4-dioxane:water (6:1, 3.5 mL) and stirred at roomtemperature under a stream of with N₂ for 5 min. The reaction mixturewas then heated to 120° C. with microwaves for 60 minutes in a sealedprocess vial. After cooling to room temperature, the reaction mixturewas diluted with ethyl acetate (20 mL) and water (20 mL), and filteredthrough Celite. The organic phase was separated and the aqueous layerwas extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine (20 mL), dried over magnesium sulfateand concentrated in vacuo. The residue was subjected to silica-gel flashcolumn chromatography [ethyl acetate-isohexane (0-100%), gradientelution]. The eluted material, obtained as a yellow solid (0.014 g,35%), was identified as4-(4-formyl-3-methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (m/z) (Method B) 357 (MH+); tR=1.10.

4-Chloro-6-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.100 g),1-methyl-1H-pyrazol-4-amine (0.080 g), sodium tert-butoxide (0.22584 g),tris(dibenzylideneacetone)dipalladium(0) (0.002 g) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.030 g) wereadded to a microwave vial, followed by dry DMF (5 mL). The reactionmixture was then flushed with N₂ for ˜10 min, and then heated to 80° C.for 1 h with microwaves. The reaction mixture was then cooled andfiltered through Celite, and the eluted material evaporated underreduced pressure. The resulting light brown solid was triturated withtoluene and then dichloromethane. The resulting yellow solid (0.064 g,50%) was identified as4-chloro-6-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 273 (M+H+); tR=1.62.

4-Chloro-6-[(pyridin-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.100 g),2-aminopyridine (0.022 g), sodium tert-butoxide (0.225 g),tris(dibenzylideneacetone)dipalladium(0) (0.002 g) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, (0.030 g)were added to a microwave vial, followed by dry DMF (5 mL). The reactionmixture was flushed with N₂ for ˜10 min, and then heated to 80° C. withmicrowaves for 1 h in a sealed process vial. The reaction mixture wasthen filtered through Celite, and the eluent concentrated under reducedpressure. The residual brown solid was triturated with dichloromethane,resulting in a beige solid (0.078 g, 62%), identified as4-chloro-6-[(pyridin-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 270 (M+H+); tR=1.24.

6-Chloro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(2.0 g, 9.43 mmol) in acetonitrile (50.0 mL) was added sodium iodide(2.83 g, 18.86 mmol) and acetyl chloride (1.47 g, 18.86 mmol). Thereaction mixture was allowed to stir at 80° C. for 24 h. Another portionof sodium iodide (2.83 g, 18.86 mmol) and acetyl chloride (1.47 g, 18.86mmol) was then added, and the reaction mixture was allowed to stir at80° C. for another 24 h. A further portion of sodium iodide (2.83 g,18.86 mmol) and acetyl chloride (1.47 g, 18.86 mmol) was then added, andthe reaction mixture was allowed to stir at 80° C. for a further 24 h(total of 72 h). Water was then added, and the resulting mixture wasextracted with ethyl acetate (3×30 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and evaporated under reduced pressure.The residue was purified by SFC, to afford6-chloro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (600 mg, 21.0%)as white solid; LC-MS (Method C) (m/z) 301.79 [M−H]⁺; tR=2.06 min.

SFC Purification Conditions

Preparative SFC was run on Waters SFC-200 system consisting of autoinjector and collector, binary pump 2545Q, UV-Visible detector model:2489 (operating at 230 nm).

Column: Ethyl pyridine (150×30) mm

Co-solvent Percentage: 15% Methanol

Total Flow: 100 mL/min

ABPR: 150 bar

UV at: 230 nm

Stack time: 3.5 min

Load/inj: 20 mg/inj

Solubility: Methanol:THF (3:1)

6-Chloro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.7 g, 2.31mmol) was taken up in dimethyl formamide (20 mL), and the temperature ofthe resulting solution was cooled to 0° C. Sodium hydride (50%, 0.14 g,3.00 mmol) was added, and the reaction mixture was stirred for 10 min.2-(Trimethylsilyl)ethoxymethyl chloride (0.46 g, 2.77 mmol) was thenadded, and the reaction mixture was allowed to stir at ambienttemperature for 2 h. On completion of the reaction (monitored by TLC),water was added and the mixture was extracted with ethyl acetate (3×30mL). The combined organic extracts were dried over anhydrous sodiumsulfate and evaporated under reduced pressure to afford6-chloro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(900 mg, 90.0%) as an off-white solid; LC-MS (Method C) (m/z) 433.81[M+H]⁺; tR=3.19 min.

6-Chloro-4-(4-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of6-chloro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(500 mg, 1.15 mmol) and 4-methyl-2-(tributylstannyl)pyridine (441 mg,1.15 mmol) in 1,4 dioxane (30 mL) were added lithium chloride (97 mg,2.30 mmol) and copper iodide (10 mg, 0.057 mmol). The reaction mixturewas degassed with nitrogen for 20 min and thentetrakis(triphenylphosphine)palladium(0) (66 mg, 0.057 mmol) was added.The reaction mixture in a sealed tube was heated at 90° C. for 18 h.After completion of the reaction (monitored by TLC), the reactionmixture was cooled to ambient temperature, poured into ice-cold waterand extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with saturated brine solution, dried over sodiumsulfate and concentrated under reduced pressure. The residue wassubjected to column chromatography using silica-gel (100-200 mesh) andeluted with 15% ethyl acetate in petroleum ether to afford 300 mg(yield: 65%) of6-chloro-4-(4-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a brown solid; LC-MS (Method C) (m/z) 399 [M+H]⁺; tR=2.97.

The following intermediate of the invention was prepared analogously:

6-Chloro-4-(6-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

300 mg obtained from6-chloro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(500 mg, 1.15 mmol) and 2-methyl-6-(tributylstannyl)pyridine (441 mg,1.15 mmol) in 65% yield; LC-MS (Method C) (m/z) 399 [M+H]⁺; tR=3.00.

6-Chloro-4-(2-methylpyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

A mixture of6-chloro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(900 mg, 2.07 mmol) and (2-methylpyridin-4-yl)boronic acid (450 mg, 2.07mmol) in 1,4-dioxane (20.0 mL) and water (4.0 mL) was degassed withnitrogen for 15 min.

Tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) and caesiumcarbonate (1.01 g, 3.11 mmol) were then added, and the reaction mixturewas allowed to stir at 100° C. in a sealed tube for 18 h. On completionof the reaction (monitored by TLC), water was added and the mixtureextracted with ethyl acetate (3×30 mL). The combined organic extractswere dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was subjected to silica-gel (100-200 mesh) columnchromatography, eluted with 30% ethyl acetate in petroleum ether, toafford compound6-chloro-4-(2-methylpyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(500 mg, 60%) as an off white solid; LC-MS (Method E) (m/z) 399 [M+H]⁺;tR=3.81.

6-Chloro-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of6-chloro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (1.5 g, 4.95mmol) and (5-methylpyridin-3-yl)boronic acid in 1,4 dioxane (10 mL) andwater (10 mL) was added potassium fluoride. The reaction mixture wasdegassed with argon for 15 min. Bis(tri-tert-butylphosphine)palladium(0)was then added, and the reaction mixture was heated at 80° C. for 18 h.After completion of the reaction (monitored by TLC), the reactionmixture was cooled to ambient temperature and filtered through a bed ofCelite. The eluent was poured into ice-cold water and extracted withethyl acetate (3×20 mL). The combined organic extracts were washed withwater, dried with sodium sulfate and concentrated under reduced pressureto afford 700 mg (yield: 53%) of6-chloro-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a pale brown solid; ¹H NMR (DMSO-d₆, 400 MHz) δ: 13.20 (1H, s), 8.65(1H, s), 8.57 (2H, s), 7.92 (1H, s), 7.44 (1H, s) 2.40 (3H, s).

6-Chloro-4-(5-methylpyridin-3-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of6-chloro-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.7 g, 2.61 mmol) in dimethyl formamide (15.0 mL) at 0° C. was addedsodium hydride (50%) (0.094 g, 3.91 mmol) and2-(trimethylsilyl)ethoxymethyl chloride (0.520 g, 3.13 mmol). Thereaction mixture was allowed to stir at ambient temperature for 2 h. Oncompletion of the reaction (monitored by TLC), water was added, and themixture was extracted with ethyl acetate (3×30 mL). The combined organicextracts were dried over anhydrous sodium sulfate and evaporated toafford6-chloro-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas off white solid (600 mg, 60%); ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.78 (1H,s), 8.664-8.660 (1H, d, J=1.6 Hz), 8.58 (1H, s), 7.93 (1H, s), 7.54 (1H,s), 5.68 (2H, s), 3.63-3.59 (2H, t, J=8.0 Hz), 2.40 (3H, s), 0.90-0.86(2H, m), −0.05 (9H, s).

6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

A mixture of 1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-amine (165 mg,0.879 mmol) and6-chloro-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(350 mg, 0.879 mmol) in 1,4-dioxane (3.0 mL) was degassed with nitrogenfor 15 min. Then tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.08mmol) was added, followed by4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (50 mg, 0.08mmol) and sodium tert-butoxide (126 mg, 1.31 mmol). The reaction mixturewas irradiated in a microwave at 100° C. for 60 min. On completion ofthe reaction (monitored by TLC), water was added and the reactionmixture was extracted with ethyl acetate (3×30 mL). The combined organicextracts were dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residual material was subjected to silica-gel(100-200 mesh) column chromatography, eluted with 50% ethyl acetate inpetroleum ether to afford6-{[1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(190 mg, 41%) as a pale yellow solid; LC-MS (Method C) (m/z) 528 [M+H]⁺;tR=2.60.

The following intermediates of the invention were prepared analogously:

6-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)amino]-4-(4-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

280 mg obtained from6-chloro-4-(4-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileand 4-chloro-1-methyl-1H-pyrazol-3-amine in 45% yield as an off-whitesolid; LC-MS (Method C) (m/z) 494 [M+H]⁺; tR=2.71.

6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(6-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

200 mg was obtained from6-chloro-4-(6-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileand 1,4-dimethyl-1H-pyrazol-3-amine in 67% yield; LC-MS (Method C) (m/z)474 [M+H]⁺; tR=2.55.

6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(6-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

190 mg was obtained from6-chloro-4-(6-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileand 1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-amine in 48% yield; LC-MS(Method C) (m/z) 528 [M+H]⁺; tR=2.93.

6-[(1-Methyl-1H-pyrazol-3-yl)amino]-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

170 mg obtained from6-chloro-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileand 1-methyl-1H-pyrazol-3-amine in 43% yield; LC-MS (Method C) (m/z) 460[M+H]⁺; tR=2.32.

6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(2-methylpyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

230 mg obtained from6-chloro-4-(2-methylpyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileand 1,4-dimethyl-1H-pyrazol-3-amine in 65% yield; LC-MS (Method C) (m/z)474 [M+H]⁺; tR=2.18.

Preparation of the Compounds of the Invention EXAMPLE 14-(3-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.1 g,0.56 mmol), 3-methoxyphenylboronic acid (0.094 g, 0.62 mmol), potassiumfluoride (0.098 g, 1.6.9 mmol), bis(tri-tert-butylphosphine)palladium(0)(0.003 g, 0.006 mmol), 1,4-dioxane (6 mL) and water (1 mL) was stirredat room temperature for 5 min under a stream of nitrogen. The stirredreaction mixture was then heated with microwaves at 150° C. for 30 minand cooled to room temperature. The reaction mixture was thenpartitioned between ethyl acetate (50 mL) and water (50 mL). The organicphase was separated, washed with water (2×20 mL), followed by brine (20mL), dried (MgSO₄) and evaporated under reduced pressure. The residuewas triturated with dichloromethane, and the residue was dried in vacuoto afford a light yellow solid (0.061 g, 44%), identified as4-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS(Method B) (m/z) 250 (MH+); tR=1.14. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.98(1H, s, br), 8.52 (1H, s), 8.44-8.43 (1H, d), 7.46-7.42 (1H, m),7.28-7.27 (1H, d), 7.19-7.16 (2H, m), 7.07-7.04 (1H, m), 3.85 (3H, s).

The following examples 2-5 were prepared analogously:

EXAMPLE 2 4-(3-Methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

0.10 g prepared from 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.20 g, 1.13 mmol) and 3-methylphenylboronic acid (0.17 g, 1.24 mmol)as an off-white solid in 38% yield. LC-MS (Method A) (m/z) 234 (MH+);tR=2.18. ¹H NMR (DMSO-d₆, 400 MHz) δ: 13.05 (1H, s, br), 8.50 (1H, s),8.43-8.42 (1H, d), 7.46-7.44 (1H, m), 7.43-7.40 (2H, m), 7.34-7.29 (1H,m), 7.25-7.24 (1H, d), 2.40 (3H, s).

EXAMPLE 3 4-(3-Ethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

0.065 g prepared from 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.10 g, 0.56 mmol) and 3-ethylphenylboronic acid (0.09 g, 0.62 mmol) asan off-white solid in 47% yield. LC-MS (Method A) (m/z) 248 (MH+);tR=2.37. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.96 (1H, s, br), 8.51 (1H, s),8.44-8.42 (1H, d), 7.48-7.41 (3H, m), 7.36-7.33 (1H, m), 7.25-7.24 (1H,d), 2.73-2.67 (2H, q), 1.27-1.24 (3H, t).

EXAMPLE 4 4-(Thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

0.023 g prepared from 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.10 g, 0.56 mmol) and thiophene-3-boronic acid as a yellow solid in18% yield. LC-MS (Method A) (m/z) 226 (MH+); tR=2.09. ¹H NMR (DMSO-d₆,400 MHz) δ: 12.94 (1H, s, br), 8.51 (1H, s, br), 8.41-8.40 (1H, d),7.93-7.92 (1H, dd), 7.75-7.73 (1H, dd), 7.48-7.47 (1H, dd), 7.30-7.29(1H, d).

EXAMPLE 54-[4-(Morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

0.078 g prepared from 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.10 g, 0.56 mmol) and 4-(4-morpholinomethyl)phenylboronic acid pinacolester hydrochloride (0.21 g, 0.62 mmol) as an off-white solid in 44%yield. LC-MS (Method A) (m/z) 319 (MH+); tR=1.54. ¹H NMR (DMSO-d₆, 400MHz) δ: 12.96 (1H, s, br), 8.51 (1H, s), 8.44-8.43 (1H, d), 7.59-7.57(2H, d), 7.47-7.45 (2H, d), 7.25-7.24 (1H, d), 3.61-3.58 (4H, m), 3.56(2H, s), 2.42-2.38 (4H, m).

EXAMPLE 64-[1-(Morpholin-4-ylmethyl)pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

1-(Benzenesulfonyl)-4-[1-(morpholin-4-ylmethyl)pyrrol-3-yl]pyrrolo[2,3-b]pyridine-3-carbonitrile(0.029 g) was taken up in tetrahydrofuran (4 mL). Water (1 mL) andpotassium carbonate (0.041 g) were added and the reaction mixture washeated to 120° C. for 30 minutes in a sealed microwave process vial. Thecooled reaction mixture was then partitioned between ethyl acetate (50mL) and brine (30 mL). The separated organic phase was then dried overmagnesium sulphate and concentrated in vacuo. The residue was thenloaded onto a 10 g silica column, and eluted on a gradient usingdichloromethane and methanol/dichloromethane (2.5:97.5). The elutedmaterial, obtained as a white solid (0.005 g, 26%), was identified as4-[1-(morpholin-4-ylmethyl)pyrrol-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 308 (MH⁺); t_(R)=1.86. ¹H NMR (DMSO-d₆, 400 MHz)δ: 12.77 (1H, s, br), 8.44 (1H, s), 8.29-8.28 (1H, d), 7.40-7.39 (1H,dd), 7.24-7.22 (1H, d), 6.95-6.94 (1H, dd), 6.59-6.58 (1H, dd), 4.75(2H, s), 3.59-3.55 (4H, m).

EXAMPLE 74-[3-Methyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

The title compound was prepared by analogy with Example 7 (usingpotassium carbonate in methanol) from1-(benzenesulfonyl)-4-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrollo[2,3-b]pyridine-3-carbonitrileto furnish a white solid.

Yield: 108 mg, 39%.

LC-MS (m/z) (Method A) 333 (MH⁺); t_(R)=1.73. ¹H NMR (DMSO-d₆, 400 MHz)δ: 12.95 (1H, s, br), 8.51 (1H, s), 8.44-8.42 (1H, d), 7.45 (1H, s),7.41-7.39 (2H, d), 7.26-7.25 (1H, d), 3.60-3.56 (4H, m), 3.52 (2H, s),2.43-2.39 (7H, m).

EXAMPLE 84-{4-[(Dimethylamino)methyl]-3-methylphenyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

The title compound was prepared analogously from Suzuki coupling with1-(benzenesulfonyl)-4-chloro-1H-pyrollo[2,3-b]pyridine-3-carbonitrileand 4-formyl-3-methylphenylboronic acid, followed by reductive aminationwith dimethylamine and de-protection with aqueous potassium carbonate(as per Example 7) to furnish a white solid. Yield: 36 mg, 53%.

LC-MS (Method A) (m/z) 291 (MH⁺); t_(R)=1.7. ¹H NMR (DMSO-d₆, 400 MHz)δ: 12.95 (1H, s, br), 8.51 (1H, s), 8.44-8.42 (1H, d), 7.44-7.35 (3H,m), 7.27-7.26 (1H, d), 3.43 (2H, s), 2.41 (3H, s), 2.20 (6H, s).

EXAMPLE 94-[3-Ethyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-[3-Ethenyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrollo[2,3-b]pyridine-3-carbonitrile(0.032 g) was taken up in methanol (10 mL) and then 10% palladium oncarbon (catalytic amount) was added. The reaction mixture was degassedwith nitrogen and then shaken under hydrogen (ambient pressure). After2.5 hours, the reaction mixture was filtered through a pad of Celite,which was then washed with further methanol. The eluent was concentratedin vacuo, and the residue subjected silica gel column chromatography.Gradient elution with dichloromethane then ethyl acetate/dichloromethane(1:1) afforded a white solid (0.012 g, 38%), identified as4-[3-ethyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 347 (MH⁺); t_(R)=1.82. ¹H NMR (DMSO-d₆, 400 MHz)δ: 12.95 (1H, s, br), 8.51 (1H, s), 8.44-8.43 (1H, d), 7.47-7.38 (3H,m), 7.27-7.25 (1H, d), 3.60-3.56 (4H, m), 3.55 (2H, s), 2.81-2.76 (2H,q), 2.43-2.38 (4H, m), 1.28-1.24 (3H, t).

EXAMPLE 104-[3-Methoxy-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

The title compound was prepared by analogy with Example 7 via Suzukicoupling with1-(benzenesulfonyl)-4-chloro-1H-pyrollo[2,3-b]pyridine-3-carbonitrileand 2-methoxy-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(Colombo et al, Org. Lett, 2007, 9, 21, 4319-4322), followed byreductive amination with morpholine and deprotection with aqueouspotassium carbonate. Yield: 0.029 g, 26%. LC-MS (Method A) (m/z) 349(MH⁺); t_(R)=1.73. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.95 (1H, s, br), 8.53(1H, s), 8.45-8.44 (1H, d), 7.49-7.47 (1H, d), 7.31-7.29 (1H, d), 7.24(1H, s), 7.19-7.17 (1H, d), 3.91 (3H, s), 3.64-3.56 (4H, m), 3.55 (2H,s), 2.46-2.39 (4H, m).

EXAMPLE 11 6-Amino-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Amino-4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.047 g),phenylboronic acid (0.060 g), potassium fluoride (0.043 g),bis(tri-tert-butylphosphine)palladium(0) (0.006 g) were suspended in1,4-dioxane:water (6:1, 3.5 mL). The reaction mixture was then stirredat room temperature and degased with nitrogen for 5 min. The reactionmixture was then heated to 120° C. for 60 minutes in a sealed microwaveprocess vial. After cooling to room temperature, the reaction mixturewas diluted with ethyl acetate (20 mL) and water (20 mL), and filteredthrough Celite. The ethyl acetate layer was separated and the aqueouslayer was extracted with ethyl acetate (3×20 mL). The combined organicphases were washed with brine (20 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by silica-gel flashchromatography [ethyl acetate-isohexane (0-100%), gradient elution]. Theeluted material, obtained as a beige solid (0.033 g, 58%) was identifiedas 6-amino-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS(Method A) (m/z) 235 (MH+); tR=1.96. ¹H NMR (DMSO-d_(b), 400 MHz) δ:12.09 (1H, s, br), 7.93 (1H, s), 7.55-7.43 (5H, m), 6.37 (1H, s), 6.09(2H, s, br).

EXAMPLE 126-Amino-4-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-(Benzylamino)-4-(3-methylphenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.063 g) was dissolved in ethanol (5 mL). 10% palladium on carbon (˜15%of starting material in weight) was added, and the reaction mixture wasshaken under hydrogen (ambient pressure) overnight. LC-MS showed thatlargely starting material remained. The solvent was removed underreduced pressure, and then acetic acid (10 mL) was added followed byfresh 10% palladium on carbon (one spatula-full). The mixture was shakenunder hydrogen (ambient pressure) overnight. Reaction mixture was thenfiltered through Celite, washed with ethyl acetate, and then evaporatedto a brown gum (0.039 g, 84%), identified as6-amino-4-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 249 (MH+); tR=2.17. ¹H NMR (DMSO-d₆, 400 MHz) δ:12.10 (1H, s, br), 7.93 (1H, s), 7.39-7.35 (2H, m), 7.33-7.30 (1H, m),7.28-7.25 (1H, m), 6.38 (1H, s), 6.08 (2H, s, br), 2.38 (3H, s).

EXAMPLE 136-[(1-Methylpyrazol-3-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-Chloro-6-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.055 g), phenylboronic acid (0.049 g), potassium fluoride (0.035 g)and bis(tri-tert-butylphosphine)palladium(0) (0.005 g) were suspended in1,4-dioxane:water (6:1, 3.5 mL). The reaction mixture was then stirredat room temperature under a stream of nitrogen for 5 min, and thenheated to 120° C. with microwaves for 60 minutes in a sealed processvial. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate (20 mL) and water (20 mL), and filteredthrough Celite. The organic phase was separated, and the aqueous layerwas extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine (20 mL), dried over magnesium sulfateand concentrated in vacuo. The residue was subjected to silica-gel flashchromatography [ethyl acetate-isohexane (0-100%)]. The eluted material,obtained as a beige solid 0.025 g (39%), was identified as6-[(1-methylpyrazol-3-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 315 (MH+); tR=2.24. ¹H NMR (DMSO-d₆, 400 MHz) δ:12.31-12.30 (1H, d, br), 9.46 (1H, s), 8.06-8.05 (1H, d), 7.57-7.46 (6H,m), 6.93 (1H, s), 6.64 (1H, d), 3.74 (3H, s).

EXAMPLE 144-(3-Methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-Chloro-6-[(1-methyl-1H-pyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.085 g), 3-methylphenylboronic acid (0.085 g), potassium fluoride(0.054 g), bis(tri-tert-butylphosphine)palladium(0) (0.008 g) weresuspended in 1,4-dioxane:water (6:1, 3.5 mL) and stirred at roomtemperature under a stream of nitrogen. The reaction mixture was thenheated with microwaves at 120° C. for 60 minutes in a sealed processvial. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate (20 mL) and water (20 mL), and filteredthrough Celite. The organic phase was extracted and the aqueous layerwas extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine (20 mL), dried over magnesium sulfateand concentrated in vacuo. The residue was subjected to silica-gel flashcolumn chromatography [ethyl acetate-isohexane (0-100%), gradientelution]. The eluted material, obtained as an off-white solid (0.028 g,27%), was identified as4-(3-methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (m/z) (Method B) 329 (MH+); tR=1.16. ¹H NMR (DMSO-d₆, 400 MHz) δ:12.28 (1H, s, br), 9.44 (1H, s), 8.05-8.04 (1H, d), 7.55-7.54 (1H, d),7.42-7.38 (2H, m), 7.35-7.32 (1H, m), 7.30-7.27 (1H, m), 6.93 (1H, s),6.65-6.64 (1H, d), 3.74 (3H, s), 2.39 (3H, s).

EXAMPLE 154-[3-Methyl-4-(morpholin-4-ylmethyl)phenyl]-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-(4-Formyl-3-methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.014 g) and morpholine (0.017 g) were dissolved in dichloroethane (5mL). Two drops of acetic acid were then added, followed by sodiumtriacetoxy borohydride. The reaction mixture was stirred at roomtemperature for 16 h. The solvent was then removed under reducedpressure, and the residue subjected to silica-gel flash columnchromatography [dichloromethane-methanol (0-10%), gradient elution]. Theeluted material, obtained as a yellow solid (0.003 g, 18%), wasidentified as4-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (m/z) (Method B) 426 (M−H+); tR=0.88. ¹H NMR (DMSO-d₆, 400 MHz) δ:12.24 (1H, s, br), 9.43 (1H, s), 8.04 (1H, s), 7.55-7.54 (1H, d),7.38-7.31 (3H, m), 6.92 (1H, s), 6.65-6.64 (1H, d), 3.74 (3H, s),3.60-3.57 (4H, m), 3.50 (2H, s), 2.43-2.39 (7H, m).

EXAMPLE 166-[(1-Methylpyrazol-4-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-Chloro-6-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.054 g), phenylboronic acid (0.027 g), potassium fluoride (0.035 g)and bis(tri-tert-butylphosphine)palladium(0) (0.00123 g) were suspendedin 1,4-dioxane-water (6:1, 3.5 mL). The reaction mixture was stirred atroom temperature under a stream of nitrogen for 5 min, and then heatedto 120° C. with microwaves for 60 minutes in a sealed process vial.After cooling to room temperature, the reaction mixture was diluted withethyl acetate (20 mL) and water (20 mL), and filtered through Celite.The organic phase was separated, and the aqueous layer was extractedwith ethyl acetate (3×20 mL). The combined organic extracts were washedwith brine (20 mL), dried over magnesium sulfate and concentrated invacuo. The residue was subjected to silica-gel flash columnchromatography [ethyl acetate-isohexane (0-100%), gradient elution]. Theeluted material, obtained as a beige solid (0.045 g, 72%), wasidentified as6-[(1-methylpyrazol-4-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 315 (M+H+); tR=1.76. ¹H NMR (DMSO-d₅, 400 MHz) δ:12.29-12.28 (1H, d, br), 9.02 (1H, s), 8.02-8.01 (2H, m), 7.58-7.45 (6H,m), 6.55 (1H, s), 3.83 (3H, s).

EXAMPLE 174-Phenyl-6-(pyridin-2-ylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

4-Chloro-6-[(pyridin-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(0.125 g), phenylboronic acid (0.113 g), potassium fluoride (0.081 g)and bis(tri-tert-butylphosphine)palladium(0) (0.012 g) were suspended in1,4-dioxane-water (6:1, 3.5 mL) and stirred at room temperature under astream of nitrogen for 5 min. The reaction mixture was then heated to120° C. with microwaves for 60 minutes in a sealed process vial. Aftercooling to room temperature, the reaction mixture was diluted with ethylacetate (20 mL) and water (20 mL), and filtered through Celite. Theorganic phase was separated and the aqueous layer was extracted withethyl acetate (3×20 mL). The combined organic extracts were washed withbrine (20 mL), dried over magnesium sulfate and concentrated in vacuo.The residue was subjected to silica-gel flash column chromatography[ethyl acetate-isohexane (0-50%), gradient elution]. The elutedmaterial, obtained as an off-white solid (0.018 g, 13%), was identifiedas4-phenyl-6-(pyridin-2-ylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.LC-MS (Method A) (m/z) 312 (M+H+); tR=1.39. ¹H NMR (DMSO-d₆, 400 MHz) δ:12.55 (1H, s, br), 9.85 (1H, s), 8.25-8.23 (1H, m), 8.19 (1H, s),8.15-8.13 (1H, m), 7.73-7.69 (1H, m), 7.61-7.48 (5H, m), 7.40 (1H, s),6.92-6.88 (1H, m).

EXAMPLE 186-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

To a solution of6-{[1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(190 mg, 0.36 mmol) in tetrahydrofuran (10.0 mL) was added triethylamine(3.0 mL) and tetra-n-butylammonium fluoride (1.0 M in tetrahydrofuran,1.8 mL, 1.80 mmol) at ambient temperature. The reaction mixture was thenheated to 75° C. and stirred for 18 h. On completion of the reaction(monitored by TLC), water was added and the reaction mixture wasextracted with ethyl acetate (3×30 mL). The combined organic layers weredried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was subjected to silica-gel (100-200 mesh) columnchromatography, eluted with 2% methanol in dichloromethane, to afford6-{[1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(100 mg, 37%) as a pale yellow solid. LC-MS (Method D) (m/z) 398 [M+H]⁺;tR=1.63 min. NMR (DMSO-d₆, 400 MHz)

δ: 12.41 (1H, br, s), 8.68 (1H, s), 8.55-8.52 (2H, m), 8.27 (1H, s),8.08 (1H, s), 7.82 (1H, s), 6.79 (1H, s), 3.83 (3H, s), 2.39 (3H, s).

The following examples 19-23 were prepared analogously:

EXAMPLE 196-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)amino]-4-(4-methylpyridin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

46 mg prepared from6-[(4-chloro-1-methyl-1H-pyrazol-3-yl)amino]-4-(4-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a pale yellow solid in 37% yield; LC-MS (Method D) (m/z) 364 [M+H]⁺;tR=1.84. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.35 (1H, s), 8.62 (1H, s),8.58-8.56 (1H, d, J=4.8 Hz), 8.05-8.04 (1H, d, J=2.8 Hz), 7.90 (1H, s),7.58 (1H, s), 7.31-7.30 (1H, d, J=4.8 Hz), 6.98 (1H, s), 3.78 (3H, s),2.41 (3H, s).

EXAMPLE 206-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

46 mg from6-[(1,4-dimethyl-1H-pyrazol-3-yl)amino]-4-(6-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a pale yellow solid in 32% yield; LC-MS (Method D) (m/z) 344 [M+H]⁺;tR=1.78. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.21 (1H, s), 8.49 (1H, s), 8.00(1H, s), 7.85-7.81 (1H, t, J=7.6 Hz), 7.51-7.49 (1H, d, J=7.6 Hz), 7.40(1H, s), 7.33-7.31 (1H, d, J=7.6 Hz), 7.02 (1H, s), 3.71 (3H, s), 2.58(3H, s), 1.88 (3H, s).

EXAMPLE 216-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

47 mg from6-{[1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(6-methylpyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilein 33% yield as an off-white solid; LC-MS (Method C) (m/z) 398 [M+H]⁺;tR=1.79. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.35 (1H, s), 8.67 (1H, s), 8.27(1H, s), 8.05-8.04 (1H, d, J=4.0 Hz), 7.87-7.82 (1H, m), 7.54-7.51 (1H,d, J=10.4 Hz), 7.35-7.327 (1H, d, J=10.4 Hz), 7.00 (1H, s), 3.84 (3H,s), 2.58 (3H, s).

EXAMPLE 226-[(1-Methyl-1H-pyrazol-3-yl)amino]-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

22 mg from6-[(1-methyl-1H-pyrazol-3-yl)amino]-4-(5-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilein 18% yield as an off white solid; LC-MS (Method D) (m/z) 330 [M+H]⁺;tR=1.51. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.34 (1H, s), 9.47 (1H, s),8.55-8.52 (2H, m), 8.08-8.07 (1H, d, J=2.8 Hz), 7.82 (1H, s),7.555-7.550 (1H, d, J=2.0 Hz), 6.96 (1H, s), 6.64-6.63 (1H, d, J=2.4Hz), 3.74 (3H, s), 2.39 (3H, s).

EXAMPLE 236-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

35 mg from6-[(1,4-dimethyl-1H-pyrazol-3-yl)amino]-4-(2-methylpyridin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carbonitrileas a yellow solid in 21% yield; LC-MS (Method D) (m/z) 344 [M+H]⁺;tR=1.45. ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.34 (1H, s), 8.56 (2H, m), 8.05(1H, s), 7.42 (1H, s), 7.40 (1H, s), 7.33-7.32 (1H, d, J=5.2 Hz), 6.82(1H, s), 3.70 (3H, s), 2.55 (3H, s), 1.88 (3H, s).

LRRK2 Wild-Type and G2019S Kinase Activity Assay

LRRK2 kinase activity is measured using a LanthaScreen kinase activityassay available from Invitrogen (Life Technologies Corporation). Theassay is a homogeneous time resolved-fluorescence resonance energytransfer (TR-FRET) assay that measures phosphorylation of afluorescein-labelled peptide substrate (fluorescein-LRRKtide,fluorescein-GAGRLGRDKYKTLRQIRQ) (SEQ ID NO 1) as a result of LRRK2kinase activity. The phosphorylated peptide is recognized by aterbium-labelled phospho-specific anti-LRRKtide antibody and,subsequently, the phosphorylated LRRKtide can be quantified by theextent of TR-FRET between the terbium donor and fluorescein acceptor.

The LRRK2 kinase is obtained from Invitrogen (Life TechnologiesCorporation) and comprises residues 970 to 2527 of the full length humanwild-type LRRK2 kinase or a similar sequence with the G2019S mutation.As discussed above, this mutation increases the kinase activity relativeto the wild-type. The kinase reactions are performed in a 20 μL volumein 384-well plates. The kinase reaction buffer consists of 50 mM Tris pH8.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA, and 2 mM DTT.

In the assay, 1 nM LRRK2 WT or 250 pM LRRK2 G2019S kinase is incubatedwith the test compound (typically at 0 to 30 μM) for 30 minutes beforethe kinase reaction is initiated by addition of 1.3 mM ATP and 0.4 μMfluorescein-LRRKtide. The reaction mixture (20 μl total volume) isincubated for 2 hours at 30° C. before the reaction is terminated byaddition of 10 mM EDTA and 1 nM terbium-labelled anti-phospho-LRRKtideantibody (final volume 20 μl). The mixture is further incubated for 30minutes at RT. TR-FRET is measured by excitation of the terbium-donorwith 340 nm light and subsequent (delay time 100 μs) measurement ofterbium and fluorescein emission at 495 nm and 520 nm, respectively,over a time window of 1000 μs. The measurement is repeated 10 times forfluorescein and 10 times for terbium emission with a 2000 μs time windowbetween repeats. TR-FRET measurements are performed on a Biomek Synergyplate. The TR-FRET signal is calculated as the emission-ratio at 520 nmover 495 nm.

The TR-FRET ratio readout for test compounds is normalized to 0%inhibition corresponding to TR-FRET ratio measured in control wells withno inhibition of the kinase activity and 100% inhibition correspondingto TR-FRET ratio measured in control wells with no kinase. Test compoundpotency (IC₅₀) was estimated by nonlinear regression using the sigmoidaldose-response (variable slope) using Xlfit 4 (IDBS, Guildford, Surrey,UK, model 205). y=(A+((B−A)/(1+((C/x)^D)))), where y is the normalizedTR-TRET ratio measurement for a given concentration of test compound, xis the concentration of test compound, A is the estimated efficacy (%inhibition) at infinite compound dilution, and B is the maximal efficacy(% inhibition). C is the IC₅₀ value and D is the Hill slope coefficient.IC₅₀ estimates were obtained from independent experiment and thelogarithmic average was calculated.

The table below shows the IC₅₀ values obtained as described above forthe exemplified compounds.

LRRK2 LRRK2 Example G2019S WT no: IC₅₀ (nM) IC₅₀ (nM) 1 201 247 2 195170 3 252 266 4 851 1279 5 1308 5442 6 650 3868 7 78 620 8 288 549 9 26149 10 154 919 11 240 216 12 17 15 13 58 48 14 2 1 15 1 4 16 164 97 17527 340 18 509 358 19 215 145 20 50 36 21 575 393 22 37 27 23 108 215

The invention claimed is:
 1. A compound of formula A

wherein R1 is an NHR2 group, R2 is H or a 5 or 6 membered heteroaromatic ring with 1 or 2 N, which heteroaromatic ring is optionally substituted with 1 or 2 groups each independently selected from the group consisting of CF₃, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkylamine and C₁-C₃ alkoxy amine, R3 is a 5 or 6 membered aromatic ring or a 5 or 6 membered heteroaromatic ring with 1 or 2 heteroatoms(s) selected from S and N, which aromatic ring or heteroaromatic ring is optionally substituted with H, 1 or 2 C₁-C₃ alkyl, or a trifluoromethyl, L is absent or represents (CH₂)_(n), n=1 or 2, R4 is H, NH₂ or a 5 or 6 membered heterocylic ring with 1 or 2 heteroatom(s) selected from N and O, which heterocyclic ring is optionally substituted with 1 or 2 C₁-C₃ alkyl, 1 or 2 C₂-C₃ alkoxy, 1 or 2 C₁-C₃ alkyl amine or 1 or 2 C₂-C₃ alkoxy amine, or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1, wherein R2 is H or a 5 or 6 membered heteroaromatic ring with 1 or 2 N, which heteroaromatic ring is optionally substituted with 1 or 2 C₁-C₃ alkyl, 1 or 2 C₁-C₃ alkoxy, 1 or 2 C₁-C₃ alkylamine or 1 or 2 C₁-C₃ alkoxy amine.
 3. A compound according to claim 1, wherein R2 represents a heteroaromatic ring selected from the group consisting of

optionally substituted with 1 or 2 groups each independently selected from the group consisting of CF₃, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkylamine and C₁-C₃ alkoxy amine, and * denotes the attachment point.
 4. A compound according to claim 1, wherein R3 is an aromatic ring selected from the group consisting of

R5 is H or C₁-C₃ alkyl; and * denotes the attachment point.
 5. A compound according to claim 1, wherein R3-L-R4 are selected from the group consisting of

R5 and R6 each independently represent H or, C₁-C₃ alkyl; and * denotes the attachment point.
 6. The compound according to claim 1, wherein R4 is

and * denotes the attachment point.
 7. The compound according to claim 1, wherein said compound is selected from the group consisting of 6-Amino-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-Amino-4-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-[(1-Methylpyrazol-3-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 4-(3-Methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 4-[3-Methyl-4-(morpholin-4-ylmethyl)phenyl]-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-[(1-Methylpyrazol-4-yl)amino]-4-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 4-Phenyl-6-(pyridin-2-ylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)amino]-4-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-{[1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]amino}-4-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 6-[(1-Methyl-1H-pyrazol-3-yl)amino]-4-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; and 6-[(1,4-Dimethyl-1H-pyrazol-3-yl)amino]-4-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.
 8. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable carriers or diluents.
 9. A compound of formula A

wherein R1 is an NHR2 group, R2 is a heteroaromatic ring selected from the group consisting of

optionally substituted with 1 or 2 groups each independently selected from the group consisting of CF₃, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkylamine and C₁-C₃ alkoxy amine, and * denotes the attachment point; R3 is a 5 or 6 membered aromatic ring or a 5 or 6 membered heteroaromatic ring with 1 or 2 heteroatoms(s) selected from S and N, which aromatic ring or heteroaromatic ring is optionally substituted with H, OH, 1 or 2 C₁-C₃ alkyl, 1 or 2 C₁-C₃ alkoxy or a trifluoromethyl, L is absent or represents (CH₂)_(n), n=1 or 2, R4 is H, NH₂ or a 5 or 6 membered heterocylic ring with 1 or 2 heteroatom(s) selected from N and O, which heterocyclic ring is optionally substituted with 1 or 2 C₁-C₃ alkyl, 1 or 2 C₂-C₃ alkoxy, 1 or 2 C₁-C₃ alkyl amine or 1 or 2 C₂-C₃ alkoxy amine, or a pharmaceutically acceptable salt thereof.
 10. A compound of formula A

wherein R1 is an NHR2 group, R2 is H or a 5 or 6 membered heteroaromatic ring with 1 or 2 N, which heteroaromatic ring is optionally substituted with 1 or 2 groups each independently selected from the group consisting of CF₃, halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ alkylamine and C₁-C₃ alkoxy amine, R3 is a 5 or 6 membered aromatic ring or a 5 or 6 membered heteroaromatic ring with 1 or 2 heteroatoms(s) selected from S and N, which aromatic ring or heteroaromatic ring is optionally substituted with H, OH, 1 or 2 C₁-C₃ alkyl, 1 or 2 C₁-C₃ alkoxy or a trifluoromethyl, L is absent or represents (CH₂)_(n), n=1 or 2, and R4 is

and * denotes the attachment point, or a pharmaceutically acceptable salt thereof. 